Factors associated with prolonged intensive care stay among self-poisoned patients

Abstract Context Since recovery or death is generally observed within a few days after intensive care unit (ICU) admission of self-poisoned patients in the developed countries, reasons for the prolonged ICU stay are of interest as they have been poorly investigated. We aimed to identify the characteristics, risk factors, outcome, and predictors of death in self-poisoned patients requiring prolonged ICU management. Methods We conducted an eight-year single-center cohort study including all self-poisoned patients who stayed at least seven days in the ICU. Patients admitted with drug adverse events and chronic overdoses were excluded. Using multivariate analyses, we investigated risk factors for prolonged ICU stay in comparison with a group of similar size of self-poisoned patients with <7day-ICU stay and studied risk factors for death. Results Among 2,963 poisoned patients admitted in the ICU during the study period, the number who stayed beyond seven days was small (398/2,963, 13.1%), including 239 self-poisoned patients (125 F/114M; age, 51 years [38–65] (median [25th-75th percentiles]); SAPSII, 56 [43–69]). Involved toxicants included psychotropic drugs (59%), cardiotoxicants (31%), opioids (15%) and street drugs (13%). When compared with patients who stayed <7days in the ICU, acute kidney injury (odds ratio (OR), 3.15; 95% confidence interval (1.36–7.39); p = .008), multiorgan failure (OR, 8.06 (3.43–19.9); p < .001), aspiration pneumonia (OR, 8.48 (4.28–17.3); p < .001), and delayed awakening related to the persistent toxicant effects, hypoxic encephalopathy and/or oversedation (OR, 8.64 (2.58–40.7); p = .002) were independently associated with prolonged ICU stay. In-hospital mortality rate was 9%. Cardiac arrest occurring in the prehospital setting and during the first hours of ICU management (OR, 27.31 (8.99–158.76); p < .001) and delayed awakening (OR, 14.94 (6.27–117.44); p < .001) were independently associated with increased risk of death, whereas exposure to psychotropic drugs (OR, 0.08 (0.02–0.36); p = .002) was independently associated with reduced risk of death. Conclusion Self-poisoned patients with prolonged ICU stay of ≥7days are characterized by concerning high rates of morbidities and poisoning-attributed complications. Acute kidney injury, multiorgan failure, aspiration pneumonia, and delayed awakening are associated with ICU stay prolongation. Cardiac arrest occurrence and delayed awakening are predictive of death. Further studies should focus on the role of early goal-directed therapy and patient-targeted sedation in reducing ICU length of stay among self-poisoned patients.


Introduction
Self-poisoning is a common cause of intensive care unit (ICU) admission, representing 2-20% of all admissions [1][2][3][4]. Selfpoisoned patients generally present fewer comorbidities and less marked severity on admission than patients admitted with other conditions [5,6]. Toxicants involved in self-poisonings requiring ICU admission in developed countries mainly include pharmaceuticals and street drugs but rarely chemicals and natural toxins, by contrast to developing countries [7,8]. To help clinicians in charge, scores and risk prediction nomograms have been developed allowing prediction of the need for ICU admission after exposure [9][10]. Well managed, ICU mortality is therefore relatively low (1-6%) in poisoned patients [1][2][3][4][5][6][7][8] by comparison to overall ICU mortality, although varying according to the type of ICU and patients and estimated at 16% (95% confidence interval, 15.5-16.9) based on an international audit of ICU patients worldwide [11] and 19% based on a European multinational observational study [6].
In the developed countries, mean length of ICU stay for poisoned patients is short, i.e., 0.5-1.5 days (mean 1.3 days) [4,5]. However, different factors contribute to prolonging ICU stay including exposure to chemicals, ethanol co-ingestion, poisoning in the elderly (65 years), elevated ICU physiological scores on admission, occurrence of aspiration pneumonia, rhabdomyolysis, thrombocytopenia and organ failure (e.g., kidney, cardiovascular and respiratory failure) [4,[12][13][14][15]. The exact reasons for ICU stay prolongation and its resulting outcome have been poorly investigated. Therefore, believing that self-poisoned patients requiring an ICU stay of sevendays or more may correspond to a very particular patient subgroup, we aimed to investigate their characteristics, outcomes and risk factors for prolonged ICU stay and in-hospital death.

Study design
We conducted a single-center cohort study including all successive self-poisoned adults who stayed for seven days or more in our ICU between November 2013 and May 2021. The study was conducted according to the Helsinki principles, declared and approved by our institutional review board. Patients were informed and invited to express their opposition to the use of their anonymized data if desired, but written consent was waived due to the retrospective and non-interventional methodology of the study.
Patients admitted in relation to drug-related adverse events and accidental overdoses were not included. Noteworthy, such patients have been shown to be older, more severely intoxicated on admission and with a higher mortality rate in comparison to self-poisoned patients [16].
Poisoned patients were managed according to standards of care [17]. Physicians in charge decided if gastrointestinal decontamination using single-or repeated-dose activated charcoal or gastric lavage should be performed and which antidote to administer and at any time.
Data were collected from the patient records and laboratory databases. Systematic blood and urinary toxicological screening was performed on a routine basis and, if relevant, drug quantifications were obtained using specific techniques. Street drugs included cocaine, amphetamines, gammahydroxybutyrate, heroin, ketamine, synthetic cathinones, poppers, and cannabis. The Simplified Acute Physiology Score (SAPS) II was calculated on admission [18]. Delayed awakening was defined as a lack of response to simple orders 48 h after sedative drug cessation or after ICU admission if the patient was not sedated [19]. Available medical, laboratory, toxicological, electroencephalography and brain imaging data were reviewed to determine the exact reasons for such delayed arousal. Organ dysfunction/failure was described based on the Sepsis-related Organ Failure Assessment (SOFA) score [20]. Multiorgan failure was defined by the presence of at least two organ failures.
To identify risk factors for prolonged ICU stay, we selected a control group of equivalent size among self-poisoned patients with short ICU stay (<7 days) during the same period. For each self-poisoned patient with 7day-ICU stay ("i"), we selected the "i þ 1" self-poisoned patient with <7day-ICU stay admitted to our ICU. If the "i þ 1" self-poisoned patient had an ICU stay of 7days (thus already included in the study), the "i þ 2" selfpoisoned patient with <7day-ICU stay was considered. Consistent with the study group, patients admitted in relation to drug-related adverse events and accidental overdoses were not included in the control group.

Statistical analysis
Data are expressed as median [25 th -75 th percentiles] and percentages as appropriate. Categorical variables were compared using Fisher's exact tests. Quantitative variables were compared using Mann-Whitney tests. Parameters significantly associated with ICU stay of 7days or death (with p < .05) based on univariate analyses were introduced into a multivariable stepwise logistic regression to identify those independently associated with prolonged ICU stay or in-hospital mortality, respectively. The threshold used for identifying factors to be included in the multivariate analysis was the best compromise between preservation of the statistical power and the possible risk of non-inclusion of a pertinent variable. Multicollinearity was tested and ruled out between all variables included in the multivariable analysis by checking that variable inflation factors were <5. Results are expressed as odds ratios (95% confidence intervals). Statistical analysis was performed using R statistical software version 3.6.3. Bilateral p values <.05 were considered as significant.

Risk factors for prolonged ICU stay
We compared our cohort of 239 self-poisoned patients with 7day-ICU stay to a control group of 239 self-poisoned patients with <7 day-ICU stay (Table 1). A significantly higher proportion of patients with self-poisoning with psychotropic agents (59% versus 48%, p ¼ .01) and cardiotoxicants (31% versus 21%, p ¼ .005) and those with multi-drug exposure (56% versus 41%, p ¼ .001) had prolonged ICU stay when compared with those who stayed less than seven days. On the other hand, a significantly higher proportion of patients who presented with ethanol overdose (6% versus 28%, p < .001) stayed for less than seven days (Figure 2

Discussion
Our study focused on critically ill self-poisoned patients with prolonged ICU stay of seven days or more. ICU stay prolongation was mainly attributed to the occurrence of poisoningattributed organ complications and delayed awakening. Our most important finding was that delayed awakening and occurrence of cardiac arrest mainly in the first hours of poisoning management represented independent predictive factors of in-hospital death while involvement of psychotropic drugs as toxicants was protective.
Characteristics of our patient population were consistent with other studies reporting ICU poisoned patients [1,2,[4][5][6][7]. However, as expected, in-hospital mortality rate (9%) in this selected cohort with prolonged ICU stay was elevated in comparison to other ICU poisoned patient cohorts, possibly also in relation to higher prevalence of cardiac morbidities, exposures to cardiotoxicants and drug-induced cardiovascular failure that can be attributed to the specificities of our department.
A proportion of patients poisoned with common toxicants such as benzodiazepines, antidepressants, ethanol and opioid stayed in the ICU for a prolonged time, suggesting that complications during the overdose even with drugs that should wear off quickly may have resulted in prolonged stay rather than the toxin per se. By comparing seven-day-versus <seven-day-ICU stay patients, we showed that aspiration pneumonia, acute kidney injury, and multiorgan failure are risk factors for prolonged ICU stay, as previously reported [4,13,14]. By contrast, cardiac arrest patients had shorter ICU stay. Although it appears paradoxical that patients who were sickest stayed for a shorter period, it is likely that the nature of the illness probably allowed earlier withdrawal of active treatment. By definition, patients with a high risk of early mortality had a reduced chance of surviving to stay in the ICU for 7 days. Interestingly, based on SAPS II scores, prolonged ICU stay patients were more severe on admission than short ICU stay patients were. Here we identified delayed awakening as additional risk factor. Contrasting with a previous finding [14], we showed that ethanol intoxication was also associated with shorter ICU stay.
In the critically ill self-poisoned patient, delayed awakening is a frequent reason for prolonged ICU stay and an independent risk factor for in-hospital mortality, as previously demonstrated [19]. Delayed awakening is either a component of coma or delirium, defined as a persistent disorder of arousal or consciousness 48 to 72 h after sedation interruption in critically ill patients. In the context of self-poisoned patients, it may be related to the prolonged pharmacological effects of self-ingested toxicants (i.e., presence of extremely high concentrations, prolonged half-life, and/or delayed clearance), or to post-anoxic encephalopathy resulting from cardiac arrest, prolonged pre-hospital hypoxemia and/or brain hypoperfusion. Rarely, delayed awakening is caused by oversedation or cerebrovascular events. Agitation, delirium and pain management and monitoring is therefore crucial in the critically ill poisoned patient, as routinely practiced in all ICU patients [21,22]. Although we almost systematically used propofol as first-line sedation in our ICU, the type and dose regimen of the chosen sedative drugs can highly influence the arousal time and should be adapted to the patient's kidney and liver functions. Sedative drugs should also be administered at the minimally effective dose, especially in the elderly, to allow optimal care and mechanical ventilation and avoid oversedation [23]. ICU nurses are advised to apply the ABCDE bundle including awakening and breathing coordination, delirium monitoring/management, and early mobility in the poisoned patients to limit complications and shorten ICU stay [24]. Brain imaging, repeated electroencephalograms and/or monitoring of the plasma concentrations of involved toxicants and ICU sedative drugs are useful to clarify the reasons for delayed awakening, as shown in several animal models [25,26].
Cardiac arrest is another major factor associated with inhospital mortality in self-poisoned patients. As shown in our series, it usually occurs early in the poisoning time-course and thus contributes to shorten hospital stay. However, if successfully resuscitated, it may be responsible for subsequent morbidities including cardiovascular failure and anoxic encephalopathy both contributing to prolong ICU stay. Selfpoisoned patient management, especially in the pre-hospital setting, should aim at minimizing the risk of cardiac arrest. Of self-intoxicated patients with cardiac arrest who survived to discharge, a previous study showed no difference in the likelihood of favorable neurological recovery whether cardiac arrest was related or not to drug overdose [27].
We observed a statistical association based on univariate analysis between street drug overdose and death, possibly resulting from increased prevalence of cardiac arrest if successfully resuscitated that led to post-anoxic encephalopathy. Due to the risks of life-threatening cardiac complications [28,29], street drug overdoses, especially those related to cocaine and amphetamines, require immediate care and close monitoring, starting from the prehospital setting. By contrast, admission in relation to psychotropic drug exposure, at lower risk of cardiovascular complications and organ failure, was associated with reduced mortality risk.
Our study has limitations. Our analysis may be underpowered, but our cohort, specifically dedicated to self-poisoned patients with prolonged ICU stay, is relatively large. The cohort is heterogeneous but reflects the real life situation in most ICUs. Organ failure was almost due to non-drug-specific mechanisms including prolonged hypotension, hypoxemia or sepsis, although, due to our retrospective study design, we could not rule out that some cases were drug-induced. Although reasonable given the number of poisoned patients admitted to the ICU during the study period (n ¼ 2963), the chosen method to select controls could have introduced biases. Finally, we acknowledge that accidental overdoses, which were excluded from our analysis may have been deliberate in some cases with patients stating it is accidental to avoid legal problems with deliberate self-harm. However, this issue was minimized by the fact that all poisoned patients have had a psychiatric consultation before ICU discharge to clarify the intentionality and suicidality of their exposure.
To conclude, acute kidney injury, multiorgan failure, aspiration pneumonia, and delayed awakening are risk factors for prolonged ICU stay in self-poisoned patients. Cardiac arrest and delayed awakening are independently associated with death in these patients, while psychotropic drug overdose is protective. Our study suggests that street drug-overdosed patients who have experienced cardiac complications resulting in prolonged ICU stay may be particularly at risk of fatal outcome. Further prospective multicenter studies should be performed to confirm our results.